What Is Currently in the Pipeline & What is Ideal for an ARV-based Prevention Candidate? Carl W. Dieffenbach, Ph.D. Director, Division of AIDS, NIAID, NIH July 18, 2011

Controlling and Ultimately Ending the HIV/AIDS Pandemic  Aggressively “seek, test and treat” infected individuals  Prevent new infections  “Cure” existing infections

FEM-PrEP HIV Prevention Study  Phase II trial testing effectiveness of oral Truvada among HIV-uninfected women  The Independent Data Monitoring Committee (IDMC) advised that the study reached futility  Conducted in Kenya, South Africa and Tanzania  Funded by USAID, with early support from Gates Foundation  Conducted by Family Health International  Full data (including drug levels) will be available later this year

July 13, 2011 Landmark Study Finds Antiretroviral Drugs Highly Effective at Preventing HIV in Both Men and Women CDC Trial and Another Major Study Find PrEP Can Reduce Risk of HIV Infection Among Heterosexuals July 13, 2011

VOICE: Vaginal & Oral Interventions to Control the Epidemic Objectives:  Estimate the effectiveness of daily tenofovir 1% gel, oral TDF, and oral FTC/TDF in preventing HIV in women  Evaluate the extended safety of daily tenofovir 1% gel, oral TDF, and oral FTC/TDF in preventing HIV in women  Evaluate adherence and acceptability to the daily vaginal and oral regiments  Assess the selection of HIV-1 drug resistance in women acquiring HIV-1 in the study

VOICE Study Design Oral TDF Oral Truvada Oral Placebo 1% Tenofovir Gel Placebo Gel 3:2 1:1:1 1: women, 1000 in each group Oral Arm Topical Arm

iPrEX OLE and San Francisco PrEP Demonstration Project  iPrEX Open Label Extension Study: Assessing adherence, drug levels and risk taking in a well- characterized cohort of trial participants after they are informed regarding the safety and efficacy of FTC/TDF PrEP and offered free open-label dosing  San Francisco PrEP Demonstration Project: Evaluating acceptability, uptake and adherence to daily PrEP among high-risk MSM in non-research settings and assessing risk behaviors before and after access to PrEP

Additional PrEP Trials  HPTN 066: Phase I, randomized, open label, pharmacokinetic study to describe the dose-proportionality and intra-individual variability of tenofovir diphosphate and emtricitabine triphosphate at steady-state in healthy volunteers taking Truvada  HPTN 067: Phase II, randomized, open label, pharmacokinetic and behavioral study of the use of intermittent oral emtricitabine/tenofovir disoproxil fumarate PrEP  HPTN 069: Phase II, randomized, double-blind, controlled four arm study of the safety, tolerability and adherence of maraviroc, maraviroc + emtricitabine, maraviroc + tenofovir, or tenofovir/emtricitabine for PrEP to prevent HIV in at-risk MSM (co-sponsored with the AIDS Clinical Trials Group)

Additional Microbicide Trials  CHOICE – Emerging from VOICE  Dapivirine ring study, MTN 020  MTN-013 – Phase I safety and pharmacokinetics of dapivirine/maraviroc intravaginal ring  Tenofovir safety studies in special populations

Next Steps – ARVs as Prevention

Next Steps for PrEP and Microbicides  Adjust VOICE based upon Partners PrEP outcomes –Move 1% Tenofovir gel to licensure –Sensitivity to adherence of the activity of PrEP for heterosexual transmission  Continue development of rectal microbicides  Define role of current products in comprehensive prevention packages  Define adherence strategies, delivery systems, and approaches to social marketing

The Dynamic Tension in the Prevention Field  Given the efficacy of treatment as prevention, what is the future niche for PrEP and microbicides in comprehensive prevention?  Do we seek to optimize what we have shown to be effective or do we seek a better next generation? –Current products are strikingly behaviorally dependent— adherence is a significant issue.  Can long acting formulations be devised— improving both treatment outcomes as well as prevention –Rings, implants, injectibles, long acting oral formulations

Optimistic, Long Range Vision  The therapeutic armamentarium will continue to improve with development and roll out of ART requiring 4-12 doses per year  PrEP would then also require 4-12 doses a year  These would be tools that can control and start ending the HIV pandemic